ASCO 2025: Evaluating Nivolumab Plus Relatlimab in Resected Stage 3 or 4 Melanoma

In the phase 3, randomized, double-blind Relativity-098 clinical trial (NCT05002569), nivolumab plus relatlimab (nivo + rela, Opdualag; Bristol Myers Squibb) did not result in significant recurrence-free survival (RFS) improvement compared with nivo alone as adjuvant treatment for the treatment of stage 3 or 4 melanoma after complete resection. These findings, presented at the 2025 American Society of Clinical Oncology (ASCO) in Chicago, Illinois, aimed to address the unmet need for more effective adjuvant therapies for individuals with completely resected melanoma.¹

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Stage 3 & 4 Melanoma

Melanoma is a form of skin cancer that begins in the melanocytes, which are cells that develop pigmentation in the skin. After an individual receives a melanoma diagnosis, doctors pinpoint how much it has spread, often using the American Joint Committee on Cancer (AJCC) TNM system, according to the American Cancer Society.²

Focusing on stages 3 and 4, which were highlighted in the phase 3 clinical trial, stage 3 is identified as a primary tumor that can be of any thickness and may or may not be ulcerated. In stage 3, the cancer spreads to nearby lymph nodes, small areas of surrounding skin, or the skin’s lymphatic channels near the tumor. In stage 4, the primary tumor can vary in thickness and may be ulcerated. Unlike stage 3, however, the cancer has spread to distant parts of the body, including the skin, lymph nodes, lungs, other organs outside the central nervous system, and the central nervous system itself.²

Treatment options for resectable stage 3 and 4 melanoma include surgical removal, adjuvant therapy, or neoadjuvant therapy, according to the Melanoma Research Alliance. Despite complete resection, individuals with advanced melanoma are at high risk of recurrence.³

Relativity-047 Clinical Trial

In a previously conducted randomized, double-blind, phase 2/3 Relativity-047 clinical trial, investigators aimed to determine whether rela + nivo was more effective than nivo by itself in treating unresectable melanoma or melanoma that has spread.⁴

The results demonstrated that the fixed-dose combination of nivo + rela showed a clinically significant improvement in progression-free survival (PFS) and overall survival (OS) compared with nivo alone, even after a 3-year follow-up, while maintaining a manageable safety profile.¹

Relativity-098 Clinical Trial

Building on the findings from the Relativity-047 study, Relativity-098 was initiated to investigate if adjuvant nivo + rela, as opposed to nivo alone, could provide a more effective treatment for individuals with completely resected stage 3 and 4 melanoma, addressing the current unmet need for improved adjuvant therapies.¹

In the study, individuals aged 12 years and older were stratified by AJCC stage 3A/3B vs 3C vs 3D/4. Following this, the individuals were randomly assigned to receive nivo 480 mg + rela 160 mg or nivo 480 mg every 4 weeks for a maximum of 1 year or until first recurrence, unacceptable toxicity, or withdrawal of consent, according to the study authors.¹

A total of 547 individuals received nivolumab plus relatlimab (nivo + rela), and 546 received nivolumab monotherapy. In the combination vs monotherapy groups, 38% vs 36% had stage 2A/B disease, and 49% vs 50% had stage 2C disease. Cutaneous nonacral melanoma was the most common subtype (80% vs 83%), followed by cutaneous acral (11% vs 10%) and mucosal melanoma (2% vs 1%). The median duration of therapy was 11.0 months in both treatment arms.¹

The results demonstrated that after a minimum follow-up of 23.4 months, there was not a statistically significant difference in RFS between the nivo + rela group and the nivo-alone group, with consistent RFS outcomes across various subgroups. Regarding the secondary end point of OS, it was not formally tested, with 148 OS events representing 48% data maturity. However, the other secondary end point of distant metastasis-free survival (DMFS) was similar in both groups.¹

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 19% of individuals receiving nivo + rela, compared to 8% in the nivo-alone group. Any-grade TRAEs led to treatment discontinuation in 17% of nivo + rela individuals and 99% of nivo-alone patients. Additionally, there were 2 treatment-related deaths in the nivo + rela group and 1 in the nivo-alone group.¹

Although the safety profile of nivo + rela was consistent with previous results from the Relativity-047 clinical trial, nivo + rela did not demonstrate significant RFS improvements.¹

REFERENCES

1. Long G., Ascierto P., Guo J., Chandra S., Nivolumab plus relatlimab vs nivolumab alone for the adjuvant treatment of completely resected stage III–IV melanoma: Primary results from RELATIVITY-098. J Clin Oncol. 43, 2025 (suppl 17; abstr LBA9500). doi: 10.1200/JCO.2025.43.17_suppl.LBA9500

2. American Cancer Society. Melanoma Skin Cancer Stages. Accessed June 9, 2025. https://www.cancer.org/cancer/types/melanoma-skin-cancer/detection-diagnosis-staging/melanoma-skin-cancer-stages.html

3. Melanoma Research Alliance. Stage 3 Melanoma. Accessed June 9, 2025. https://www.curemelanoma.org/about-melanoma/melanoma-staging/stage-3

4. A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma (RELATIVITY-047). ClinicalTrials.gov: NCT03470922. Updated: March 17, 2025. Accessed June 9, 2025. https://clinicaltrials.gov/study/NCT03470922